Exposure-response analysis of oral and intravenous imatinib in critically ill patients with COVID-19 acute respiratory distress syndrome
Bibliographic record
Abstract
• This study investigates how unbound and total imatinib and DM-imatinib, relate to clinical outcomes in critically ill COVID-19 ARDS patients. • Despite higher total imatinib exposure in ICU patients, unbound drug levels were similar to less severe cases, yet no clear link was found between imatinib exposure and clinical improvement or mortality. • Disease severity and altered protein binding affect imatinib pharmacokinetics in critical COVID-19, highlighting the importance of focusing on unbound drug concentrations to guide dosing in future trials. Imatinib, initially approved for chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST), was investigated in two randomized placebo-controlled trials for its potential effect on COVID-19-related ARDS (C-ARDS). A known relationship between imatinib concentrations and effectiveness exists in CML and GIST, but this is uncharacterized in critically ill C-ARDS patients, where standard dosing may not be suitable. This study aims to explore the association between unbound imatinib, total imatinib, and total N-desmethyl-imatinib exposure with clinical outcomes in critically ill C-ARDS patients. This post-hoc analysis included C-ARDS patients from the CounterCOVID and InventCOVID trials, all requiring invasive ventilation. In the CounterCOVID trial, patients received 800 mg imatinib on day 1, followed by 400 mg once daily for 9 days. In InventCOVID, the dose was 200 mg intravenously twice daily for 7 days or until ICU discharge. A pharmacokinetic (PK) model simulated the concentration-time profiles of total imatinib (T), unbound imatinib (U), and the sum of total imatinib plus its metabolite desmethyl-imatinib (PM). PK samples were used to estimate individual PK parameters, after which associations with clinical outcomes (WHO score, P/F ratio, ICU stay, ventilator-free days, and mortality) were tested using linear mixed models and regression analysis. Data from 53 patients revealed that critically ill patients reached higher total imatinib exposure but similar unbound imatinib exposure compared to others. Critical illness and concurrent treatments influenced imatinib exposure. No clear exposure-response relationship was found between imatinib exposure and clinical outcomes. Although critical illness was linked to higher imatinib exposure, no exposure-response relationship was found. Disease severity may have also impacted the drug’s effectiveness, suggesting that ICU patients may require adjusted dosing. Future clinical studies of repurposed drugs should focus on exposure-response relationships to better understand optimal dosing in new patient populations, particularly for highly protein-bound drugs. ClinicalTrials.gov Identifier: NCT04794088, registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.006 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".